Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND To describe a large series of patients with α, β and γ sarcoglycanopathies (LGMD-R3, R4 and R5) and study phenotypic correlations and disease progression. METHODS A multicentric retrospective study in 4 centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS 100 patients (54 γ-SG; 41 α-SG; 5 β-SG) from 80 families were included. γ-SG patients had earlier disease onset than α-SG patients (5.5 vs 8 years, p=0.022) and β-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% β-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p=0.01). Thirty patients were ventilated and 6 died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time-to-LoA (p=0.021 and p=0.002). Age at onset was an independent predictor of both severity and time-to-LoA (p=0.0004 and p=0.009). α-SG patients showed genetic heterogeneity, while >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSION This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA and should be taken into account in future clinical trials.